Human Papillomavirus (HPV) is a very common virus that is transmitted through direct contact. It is non-enveloped double stranded DNA virus that lives in the keratinocytes of the skin and mucus membranes. These infections are most often asymptomatic. However, a small percentage of infections lead to warts (AKA Verrucae) that usually presents with a raised round rough cauliflower lesion. These lesions are formed by a benign epithelial proliferation of the basal keratinocytes. This should make sense since we covered in our cancer video that the term papilloma means a benign outwardly projecting overgrowth with finger-like projections. Warts usually don’t cause pain, bleeding, or itching. There are about 10 different subtypes of wart based on their appearance and predilection for certain areas of the body, but that is beyond the scope of the step 1 exam. There are also roughly 200 different serotypes of the virus. We will discuss a few specific high yield serotypes, but for the most part this is also beyond the scope of the exam.
A large majority of warts regress spontaneously over the course of weeks or months. The body is usually able to clear the virus without medical intervention. However, clearance of the virus does not necessarily confer immunity to future infections. If the wart causes an unwanted cosmetic appearance it can be removed through a number of different techniques including cryotherapy (freezing) & topical salicylic acid (an active metabolite of aspirin).
HPV is the most common Sexually Transmitted Infection (STI/STD) worldwide, and is associated with genital warts and various types of genital cancer. Condyloma Acuminatum is a genital wart caused by HPV. HPV serotypes 6 & 11 are most often associated with genital warts, but rarely associated with genital cancers. However, patients can be infected by multiple subtypes at once so the presence of warts does not rule of cancer.
HPV is associated with cancers of the vagina, vulva, penis, and even the oropharynx (I’ll leave it to your imagination to figure out how the virus gets there). However, your focus should be on cervical cancer, because it is by far the most common. There are about a dozen subtypes of Human Papilloma Virus that are considered high risk for genital cancers, but serotypes 16 & 18 are discussed most on exams.
While in most patients the virus is cleared relatively quickly in some patients the virus can remain as an active subclinical/asymptomatic infection for many years. Over time (often over a decade) these persistent infections are the ones that can lead to cancer. Cancers arise as a result of the viral genome being integrated into the host cell’s DNA. In particular, genes coding for E6 & E7 oncogenes are carcinogenic. These viral proteins inactivate tumor suppressors leading to unregulated cell division. In particular E6 inactivates p53 and E7 inactivates rb.
Since it takes many years for the viral infection to turn into cancer and early interventions improve outcomes Papillomavirus is an excellent target for screening. A PAP Smear (AKA PAP Test) is a screening test used to look at cells of the cervix in hopes of identifying pre-cancers and cancers before they can become malignant. Using a small brush cells of the transitional zone (where the outer squamous cells “transition” into the inner glandular columnar cells) are removed so they can be examined under a microscope. This transitional zone is the most common location of cervical cancer and represents an area of physiologic metaplasia. Koilocytes (AKA Koilocytic Atypia) are irregular squamous epithelial cells seen on PAP smears that can signify HPV infection. These cells have an enlarged darkened nucleus, perinuclear clearing/halo, and an irregular border. A PAP Smear may be combined with an HPV DNA test which can help identify specific high risk subtypes of the virus and if negative may allow you to decrease the frequency of PAP Smears. There is currently a debate about the best frequency of PAP Smears as well as the age that they should be started and discontinued. Therefore, you will see different numbers depending on what guideline you are looking at. The USPSTF recommends PAPs every 3 years from age 21 to 65 or every 5 years after age 30 if the PAP Smear is combined with negative DNA testing.
Interpreting the results of the PAP and determining the follow up testing and/or treatment follows some pretty complicated algorithms and is therefore largely beyond the scope of the Step 1 exam. You just need to know the basics. If the results are normal or negative the patient just needs the normal PAP Smear follow up in a few years. If the results are inconclusive, such as Atypical Squamous Cells of Undetermined significance (ASC-US), the patient will need closer follow up with repeat testing. Clearly atypical results, such as Low Grade Squamous Intraepithelial Lesions (LSIL) or High Grade Squamous Intraepithelial Lesions (HSIL), will likely require additional testing such as colposcopy or biopsy.
There are now vaccines that protects against some of the most common strains of HPV. These recombinant vaccines, which go by trade names like Gardasil, help prevent against certain serotypes of the virus such as 16 & 18. These vaccines are only effective before individuals are exposed to the virus and therefore are recommended primarily for teenagers. These vaccines are particularly important in females, but are also recommended for males in order to reduce their risk of transmitting HPV to partners as well as decreasing there risk for genital warts and penile cancer. PAP Smears are still required for females even after receiving the vaccine as it does not prevent all serotypes of HPV.
Parvovirus B19 is a non-enveloped (naked) single stranded DNA virus that infects the red blood cell precursors in the bone marrow. The most common presentation of Parvovirus B19 is Erythema Infectiosum, or Fifths Disease, in school aged children. This is when a child has a “Slapped Cheek” red rash on their cheeks that later spreads to the trunk and upper extremities. There can be a prodromal period of fever, fatigue, and upper respiratory symptoms lasting for a few days before the appearance of the rash. It was originally named fifths disease because at the time it was the fifth most common cause of red rash in children.
Adults do not get Fifth Disease, but can present with joint pain often with a history of exposure to a child with Fifth Disease. Healthy adults may also have a mild temporary anemia due to Parvovirus, but this is usually subclinical because healthy individuals have a “reserve” of red blood cells. Individuals with hematologic comorbidities are at particularly high risk of anemia, because their erythropoiesis (production of red blood cells) is already being stressed. For example, individuals with Sickle Cell Disease or Hereditary Spherocytosis are dependent on a near constant production of red blood cells, due to the high rate or RBC destruction. These individuals cannot handle even a few days of decreased RBC production. This scenario of profound anemia is often referred to as an Aplastic Crisis (AKA Reticulocytopenia).
Parvovirus can cross the placenta and is one of the TORCH infections (it is the O for other). I’m gonna hold off on talking about that until a later video dedicated entirely to TORCH infections.
Adenovirus is a non-enveloped (naked) double stranded DNA virus that is primarily spread via respiratory droplets. It is mostly seen in children, but also occasionally in adults. It is usually seen with children in close contact with many other kids like at day care or camp. Historically severe infections were seen in the military often during basic training. The US used an adenovirus vaccine in the past, but it has since been discontinued. Adenovirus primarily presents as Pharygoconjunctivitis. This can include pharyngitis (sore throat), conjunctivitis (inflamed eyes), fever and lymphadenopathy. Adenovirus can cause the clinical picture commonly referred to as the “common cold,” however there are many other viruses that cause this clinical picture. It should come as no surprise that Adenovirus got its name when it was originally identified in the adenoids (or tonsils). While Adenovirus is most often causes a mild self-limited infection it can also cause more serious respiratory infections or serious infections of other organ systems especially in the immunocompromised.
- “Deep plantar wart” by Marionette available at https://commons.wikimedia.org/wiki/File:Deep_plantar_wart.jpg via Creative Commons Attribution-Share Alike 3.0 Unported License
- Derivative of “ThinPrep Pap smear HPV” by Ed Uthman MD available at https://commons.wikimedia.org/wiki/File:ThinPrep_Pap_smear_HPV.jpeg via Public Domain
- Derivative of “14 month old with Fifth Disease” by Sandyjameslord available at https://commons.wikimedia.org/wiki/File:14_month_old_with_Fifth_Disease.jpg via Creative Commons Attribution-Share Alike 4.0 International License
- Derivative of “Fifth Disease” by Andrew Kerr available at https://commons.wikimedia.org/wiki/File:Fifth_disease.jpg via Public Domain